12228 Chem. Commun., 2012, 48, 12228–12230 This journal is c The Royal Society of Chemistry 2012

Cite this: Chem. Commun., 2012, 48, 12228–12230

Double nucleophilic attack on isocyanide carbon: a synthetic strategy

for 7-aza-tetrahydroindolesw

Yifei Li, Xianxiu Xu,* Chunyu Xia, Lingjuan Zhang, Ling Pan and Qun Liu*

Received 15th August 2012, Accepted 30th October 2012

DOI: 10.1039/c2cc35896d

A novel and efficient route for the synthesis of 7-aza-tetra-

hydroindoles from N-aryl/alkyl-alkenoylacetamides and ethyl

isocyanoacetate is described. A mechanism, involving a stepwise

[3+2] cycloaddition–intramolecular aza-Michael addition cascade,

is proposed that explains the origin of the double nucleophilic

attack on the isocyanide carbon atom.

In organic synthesis, the one-pot tandem strategy is used to

improve the efficiency of a chemical reaction whereby multiple

bonds are formed in a single reaction without the need to isolate

intermediates.1 As part of our research to develop divinyl ketones

(DVKs) as 1,5-dielectrophiles for the construction of diverse

carbo- and heterocyclic structures,2 we recently reported the

one-pot synthesis of highly substituted phenols,3a 2,3-dihydro-

4-pyridones,3b pyrrolizidines,3c and C2-tethered pyrrole/oxazole

pairs,4 via a [5+1] annulation (inter-/intramolecular Michael

addition sequence). For example, catalyzed by DBU (DBU =

1,8-diazabicyclo[5.4.0]undec-7-ene), the reaction of DVKs 1 with

ethyl isocyanoacetate 2 can lead to C2-tethered pyrrole/oxazole

pairs in moderate to high yields in the case of R1 is an aryl

group (Scheme 1). Whereas, under identical conditions, highly

functionalized 7-aza-tetrahydroindole 3a is produced in 61%

yield from the reaction of DVK 1a bearing a bulky t-Bu R1

group. In the reaction, the ketene dithioacetal moiety is intact.4 To

our knowledge, the construction of 3amentioned above represents

the first example of one-pot synthesis of 7-aza-tetrahydroindoles

from readily available acyclic precursors, which prompted us

to find an efficient route to their synthesis from identical

starting materials (i.e., N-aryl/alkyl-alkenoylacetamides (1)4,5

and ethyl isocyanoacetate (2))6 by catalyst variation.

The construction of distinct types of complex molecules

from identical starting materials is an attractive and challenging

task in organic synthesis.7 On the other hand, although isocyanides

have found a wide range of applications due to the dual

electrophilic and nucleophilic character of the isocyanide

carbon atom,6 the development of new trends in the field of

isocyanide-based reactions occupies a unique position in organic

synthesis.3c,4,6 Furthermore, the synthesis of the azacyclic systems

related to 7-aza-tetrahydroindoles 3 is crucial since several

alkaloids8–11 including chaetominine8 and neoxaline (Fig. 1)9

have shown significant biological activities. In their synthesis,

a key step to form the bicyclic aminal system was realized

through aza-cyclization via the corresponding 2-haloindole

intermediates.8b,c,10 Very recently, a four-step synthesis to

7-aza-tetrahydroindoles starting from N-alkylated a-bromo-

acetamides was described.12 However, the direct synthesis of

this heterocyclic skeleton remains a challenge.8–12 The study

described here reveals that 7-aza-tetrahydroindoles 3 (Table 2)

and 6 (Scheme 3) can be synthesized in a single step from the

reactions of ethyl isocyanoacetate 2 with a range of readily

available N-aryl/alkyl-alkenoylacetamides 14,5 and 55,13 in an

atom economical manner under mild conditions.

Different from the formation of C2-tethered pyrrole/oxazole

pairs involving a [5+1] annulation intermediate, the formation of

a pyrroline intermediate via [3+2] cycloaddition of the enone

moiety of 1 is required for the synthesis of 7-aza-tetrahydroindoles

(Scheme 1).4 In this research, initially, the reaction of 1a (R1 =

t-Bu, R2 = Tol) with ethyl isocyanoacetate 2 was attempted in

the presence of AgOAc to test the possibility of the stepwise

[3+2] cycloaddition of the enone moiety of 1a.14 However,

catalyzed by AgOAc (0.1 equiv.), no reaction was observed by

treatment of 1a (1.0 mmol) with 2 (1.2 equiv.) in acetonitrile

(5 mL) at room temperature for long reaction times due to the

Scheme 1 Reactions of DVKs 1 with 2 under basic conditions.

Fig. 1 Structures of chaetominine and neoxaline.

Department of Chemistry, Northeast Normal University, Changchun130024, China. E-mail: xuxx677@nenu.edu.cn, liuqun@nenu.edu.cn;Fax: +86 431 85099759; Tel: +86 431 85099759w Electronic supplementary information (ESI) available: Experimentaldetails and spectral data for 3, 4b and 6. See DOI: 10.1039/c2cc35896d

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This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 12228–12230 12229

bulky t-Bu R1 group (Scheme 2A). Gratifyingly, under similar

conditions, pyrroline 4b could be obtained in 50% yield (1 : 1

mixture of trans to cis isomer)14a from 1b (R1 = p-ClC6H4,

R2=Tol) and 2 at 10 1C for 24 h, along with the recovery of 45%

of 1b (Scheme 2B).15 Subsequently, it was found that treatment of

diastereopure 4b15 with K2CO3 led to 7-aza-tetrahydroindole

3b in a diastereospecific manner and in quantitative yield via

intramolecular aza-Michael addition (Scheme 2C).4,5

A comparison of the above results with previous studies4

indicates that the reaction pathways of 1 with 2 could be tuned

by varying only the catalyst (Scheme 2B versus Scheme 1).7

Encouraged by the above results (Schemes 2B and C), we

further examined the reaction of 1b with 2 in the presence of

AgOAc and a suitable base aiming at the synthesis of 7-aza-

tetrahydroindoles 3 in one-pot. Indeed, catalyzed by AgOAc

(0.1 equiv.) and K2CO3 (0.2 equiv.), 3b was obtained in 97%

yield from the reaction of 1b (1.0 mmol) with 2 (1.2 equiv.) in

acetonitrile (5 mL) at room temperature for only 1.5 h

(Table 1, entry 2). Further optimization of reaction conditions

allowed us to find that 3b could be obtained in nearly

quantitative yield within shorter reaction time when DBU

was employed as the base (Table 1, entry 1). In comparison,

Cu(OAc)2 was a less effective catalyst than AgOAc (Table 1,

entry 4). However, under optimized conditions (Table 1, entry 1),

no reaction occurred between 1a and 2 even after long reaction

times (24 h, Scheme 2A) due to the steric hindrance of the

bulky t-Bu group.16

Further experiments showed that the reaction proceeded

more efficiently for various N-aryl-alkenoylacetamides 1 under

optimal conditions (Table 1, entry 1) and the results are

summarized in Table 2. For example, the reactions of ethyl

isocyanoacetate 2 with 1b–j (R2 = Tol) having an alkyl (entry 8),

styrenyl (entry 9), phenyl (entry 2), electron-rich (entries 3–5) and

electron-deficient aryl (entries 1 and 7), or heteroaryl R1 group

(entry 6) can afford the corresponding 7-aza-tetrahydroindoles

3b–j in excellent yield under very mild conditions. In addition,

under identical conditions, the reactions of 2 with 1k and 1l

(R2 = Ph) gave 7-aza-tetrahydroindoles 3k and 3l, respectively,

in excellent yield (entries 10 and 11). In the cases of 1m–o bearing

an alkyl R2 group, the desired 7-aza-tetrahydroindoles 3m–o

were also prepared in high yield (entries 12–14) by treatment of

1m–o and 2 with AgOAc (0.1 equiv.) and DBU (0.5 equiv.) for

2–3 h before adding another portion of DBU and stirring for

additional 5 h. In comparison, only the corresponding formal

[3+2] cycloaddition adducts 4m–o were formed without the

addition of additional DBU due to the weaker acidity of N-alkyl

amides than N-aryl amides (entries 1–11 versus entries 12–14).5

The tandem process mentioned above represents a simple

and efficient methodology for the construction of 7-aza-tetra-

hydroindoles.8–12 The starting materials are readily available

acyclic precursors4,5 and the reaction is 100% atom-economic.1

To test the generality of this new reaction, the reactions of

selected 1-cinnamoylcyclopropanecarboxamides (5)5,13 with 2

were further investigated. However, the reaction of 5a (R =

4-ClC6H4) with 2 under above conditions (Table 1, entry 1) for

48 h gave 7-aza-tetrahydroindole 6a in only 30% yield. After

further optimization of the reaction conditions, the desired

products 6a–c were obtained in 81, 85 and 78% yield, respec-

tively, by treating the corresponding 5 (1.0 mmol) and 2

(1.2 equiv.) with AgOAc (0.1 equiv.) and DBU (1.0 equiv.) in

acetonitrile at room temperature for 24 h (Scheme 3). The

results requiring stoichiometric amounts of DBU for substrates

5 (Scheme 3) and catalytic amounts of DBU for substrates 1 are

Scheme 2 Reactions of 1 in the presence of AgOAc.

Table 1 Optimization of reaction conditions

EntryCat. (equiv.)/base (equiv.) T (1C) T (h) Yielda (%)

Ratiotrans/cisb

1 AgOAc (0.1) rt 1.0 99 57 : 43

DBU (0.2)

2 AgOAc (0.1) rt 1.5 97 55 : 45K2CO3 (0.2)

3 AgOAc (0.1) 10 24 72 50 : 50K2CO3 (0.2)

4 Cu(OAc)2 (0.1) 80 5 48 50 : 50DBU (0.2)

a Isolated yield. b Determined by 1H NMR.

Table 2 Synthesis of 7-aza-tetrahydroindoles 3

Entry 1 R1 R2 Time (h) 3 Yielda (%) trans/cis

1 b 4-ClC6H4 Tol 1.0 b 99 57 : 432 c Ph Tol 2.0 c 98 50 : 503 d Tol Tol 5.0 d 98 52 : 484 e 4-MeOC6H4 Tol 6.0 e 99 51 : 495 f 3,4-O2CH2C6H3 Tol 2.0 f 99 34 : 666 g 2-Furyl Tol 5.0 g 97 55 : 457 h 4-BrC6H4 Tol 2.0 h 93 38 : 628 i Cyclohexyl Tol 4.0 i 93 53 : 479 j PhCHQCH Tol 4.5 j 98 45 : 5510 k 4-ClC6H4 Ph 8.0 k 90 42 : 5811 l Ph Ph 2.5 l 97 59 : 4112b m 4-ClC6H4 Me 7.0 m 80 59 : 4113b n Ph Me 7.0 n 76 52 : 4814b o Tol Me 8.0 o 78 55 : 45

a Isolated yields. b Reaction conditions: adding DBU (0.5 equiv.) and

stirring for 2–3 h and then adding another portion of DBU (1.0 equiv.)

and stirring for additional 5 h.

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12230 Chem. Commun., 2012, 48, 12228–12230 This journal is c The Royal Society of Chemistry 2012

in accordance with our previous report for the synthesis of

fused oxazolines.17

Taking together the previous4–6,13a,14 and present results

(Table 2, Schemes 2 and 3), a plausible mechanism for the

formation of 7-aza-tetrahydroindoles 3 and 6 may involve

(Scheme 4, with the reaction of 1 with 2 as an example): (1)

the formation of pyrroline intermediate 4 in a regiospecific

manner from AgOAc catalyzed stepwise [3+2] cycloaddition

of the enone moiety of 1 and ethyl isocyanoacetate 2

(Scheme 2B)14a and (2) base-catalyzed intramolecular aza-Michael

addition of the pyrroline intermediate to form 7-aza-tetra-

hydroindoles 3 (Scheme 2C).5,13a Based on the experimental

results for the selective formation of either C2-tethered pyrrole/

oxazole pairs4 or 7-aza-tetrahydroindoles 3 and 6 (Table 2 and

Scheme 3), it is important to emphasize that the addition of

catalytic amounts of AgOAc can lead to markedly different

regioselectivity. In the absence of AgOAc, the C2-tethered

pyrrole/oxazole pairs would be formed from 1 and 2 via a

[5+1] annulation intermediate 7 (Scheme 4, box).4

In conclusion, we have developed a new atom economical

strategy for the synthesis of various highly functionalized

7-aza-tetrahydroindoles from easily available N-aryl/alkyl-

alkenoylacetamides and ethyl isocyanoacetate in a single step

under mild conditions. A new reaction mechanism, stepwise

[3+2] cycloaddition–intramolecular aza-Michael addition

sequence, is proposed. Further studies are in progress.

Financial support of this research provided by the NNSFC

(21272034, 21172030 and 21072027) and the Fundamental

Research Funds for the Central Universities (09 QNJJ017

and 12QNJJ010) is greatly acknowledged.

Notes and references

1 For reviews on tandem reactions, see: (a) L. F. Tietze, H. P. Bell andG. Brasche, Domino Reactions in Organic Synthesis, Wiley-VCH,Weinheim, 2006; (b) D. Enders, C. Grondal and M. R. M. Huttl,Angew. Chem., Int. Ed., 2007, 46, 1570; (c) K. C. Nicolaou,T. Montagnon and S. A. Snyder, Chem. Commun., 2003, 551;(d) A. Padwa and S. K. Bur, Tetrahedron, 2007, 63, 5341.

2 For recent reviews, see: (a) L. Pan and Q. Liu, Synlett, 2011, 1073;(b) L. Pan, X. Bi and Q. Liu, Chem. Soc. Rev., DOI: 10.1039/C2CS35329F.

3 (a) X. Bi, D. Dong, Q. Liu, W. Pan, L. Zhao and B. Li, J. Am.Chem. Soc., 2005, 127, 4578; (b) D. Dong, X. Bi, Q. Liu andF. Cong, Chem. Commun., 2005, 3580; (c) J. Tan, X. Xu, L. Zhang,Y. Li and Q. Liu, Angew. Chem., Int. Ed., 2009, 48, 2868.

4 Y. Li, X. Xu, J. Tan, C. Xia, D. Zhang and Q. Liu, J. Am. Chem.Soc., 2011, 133, 1775.

5 Y. Li, X. Xu, J. Tan, P. Liao, J. Zhang and Q. Liu, Org. Lett.,2010, 12, 244.

6 For recent reviews, see: (a) A. V. Lygin and A. de Meijere, Angew.Chem., Int. Ed., 2010, 49, 9094; (b) A. V. Gulevich, A. G. Zhdanko,R. V. A. Orru and V. G. Nenajdenko, Chem. Rev., 2010, 110, 5235;(c) J. Campo, M. Garcia-Valverde, S. Marcaccini, M. J. Rojo andT. Torroba, Org. Biomol. Chem., 2006, 4, 757.

7 For recent reports, see: (a) B. Alcaide, P. Almendros and T. M. delCampo, Angew. Chem., Int. Ed., 2007, 46, 6684; (b) X. Jiang,X. Ma, Z. Zheng and S. Ma, Chem.–Eur. J., 2008, 14, 8572;(c) L. Liu and J. Zhang, Angew. Chem., Int. Ed., 2009, 48, 6093;(d) A. S. Dudnik, Y. Xia, Y. Li and V. Gevorgyan, J. Am. Chem.Soc., 2010, 132, 7645; (e) P. A. Evans, J. R. Sawyer andP. A. Inglesby, Angew. Chem., Int. Ed., 2010, 49, 5746;(f) P. Panne and J. M. Fox, J. Am. Chem. Soc., 2007, 129, 22.

8 (a) R. H. Jiao, S. Xu, J. Y. Liu, H. M. Ge, H. Ding, C. Xu,H. L. Zhu and R. X. Tan, Org. Lett., 2006, 8, 5709;(b) B. Malgesini, B. Forte, D. Borghi, F. Quartieri, C. Gennariand G. Papeo, Chem.–Eur. J., 2009, 15, 7922; (c) M. Toumi,F. Couty, J. Marrot and G. Evano, Org. Lett., 2008, 10, 5027.

9 T. Sunazuka, T. Shirahata, S. Tsuchiya, T. Hirose, R. Mori,Y. Harigaya, I. Kuwajima and S. Ohmura, Org. Lett., 2005,7, 941, and references therein.

10 For kapakahines, see: T. Newhouse, C. A. Lewis, K. J. Eastmanand P. S. Baran, J. Am. Chem. Soc., 2010, 132, 7119.

11 For perophoramidine, see: (a) S. M. Verbitski, C. L. Mayne,R. A. Davis, G. P. Concepcion and C. M. Ireland, J. Org. Chem.,2002, 67, 7124; (b) J. R. Fuchs and R. L. Funk, J. Am. Chem. Soc.,2004, 126, 5068; (c) H. Wu, F. Xue, X. Xiao and Y. Qin, J. Am.Chem. Soc., 2010, 132, 14052.

12 N. Oukli, S. Comesse, N. Chafi, H. Oulyadi and A. Daıch,Tetrahedron Lett., 2009, 50, 1459.

13 (a) F. Liang, S. Lin and Y. Wei, J. Am. Chem. Soc., 2011,133, 1781; (b) Z. Zhang, Q. Zhang, S. Sun, T. Xiong and Q. Liu,Angew. Chem., Int. Ed., 2007, 46, 1726.

14 (a) R. Grigg, M. I. Lansdell and M. Thornton-Pett, Tetrahedron,1999, 55, 2025; (b) S. Kamijo, C. Kanazawa and Y. Yamamoto,J. Am. Chem. Soc., 2005, 127, 9260; (c) A. V. Lygin, O. V. Larionov,V. S. Korotkov and A. de Meijere, Chem.–Eur. J., 2009, 15, 227;for a review on silver-mediated synthesis of heterocycles, see: (d) M.Alvarez-Corral, M. Munoz-Dorado and I. Rodırguez-Garcıa,Chem. Rev., 2008, 108, 3174.

15 Diastereomers 4b were completely separable by silica columnchromatography.

16 In the presence of DBU (1.0 equiv.) and AgOAc (0.1 equiv.), 7-aza-tetrahydroindole 3a could be obtained in 60% yield when thereaction of 1a (1.0 mmol) with 2 (1.2 equiv.) was performed inacetonitrile (5 mL) at 80 1C for 7 h.

17 L. Zhang, X. Xu, J. Tan, L. Pan, W. Xia and Q. Liu, Chem.Commun., 2010, 46, 3357.

Scheme 3 Synthesis of 7-aza-tetrahydroindoles 6.

Scheme 4 Proposed mechanism for the formation of 3.

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